Schizophrenia breakthrough: scientists shed light on biological cause

What causes schizophrenia? This is a question that has challenged scientists since the disorder was first identified almost 130 years ago. Now, for the first time, researchers have shed light on the biological origin of the illness.

Researchers have found that variants of the gene C4 - shown in green - play a key role in the development of schizophrenia.Image credit: Heather de Rivera/McCarroll

In what has been hailed a "breakthrough" in schizophrenia research, scientists from Harvard Medical School, the Broad Institute and Boston Children's Hospital - all in Massachusetts - have discovered how a gene called complement component 4 (C4) plays a key role in schizophrenia development.

The research team - including senior author Steven McCarroll, associate professor of genetics and director of genetics for the Stanley Center at Harvard - says their findings may aid the development of much-needed new treatments and preventive strategies for schizophrenia.

It is estimated that around 21 million people across the globe have schizophrenia, with symptom onset most common in late adolescence or early adulthood.

The illness was first discovered by German psychiatrist Dr. Emile Kraepelin in 1887, though the term "schizophrenia" was not used until 1910, coined by Swiss psychiatrist Paul Eugen Bleuler. The name came from the Greek words "schizo" (split) and "phren" (mind), fueling the myth that people with schizophrenia have split personalities; this is not the case.

Understanding the genetic roots of schizophrenia

In the years since schizophrenia was discovered, researchers have been working hard to determine the underlying biological mechanisms that cause the illness.

Lack of understanding in this area has hampered the discovery of a cure or preventive strategies for schizophrenia; current treatments - such as antipsychotic medications - can only focus on eliminating symptoms.

Increasingly, researchers have looked at how schizophrenia may be caused by genetic factors, based on the knowledge that the disorder is heritable. In July 2014, the Schizophrenia Working Group of the Psychiatric Genomics Consortium - including investigators from the Stanley Center - identified more than 100 areas of the human genome that are linked to the disorder.

Now, McCarroll and colleagues have built on these findings, identifying a specific gene that appears to have the strongest association with schizophrenia risk. This gene is C4, which is already known to play a key role in the immune system, alerting immune cells to pathogens that need to be destroyed.

Specific C4 structures linked to increased schizophrenia risk

For their study, recently published in the journal Nature, the team set out to gain a better understanding of how C4 works in the brain.

McCarroll and his colleague Aswin Sekar, an MD/PhD student at Harvard Medical School, created a novel molecular technique that enabled the team to characterize the structure of the C4 gene in the DNA samples of more than 65,000 individuals, of whom around 29,000 had schizophrenia and 36,000 did not.

The researchers explain that C4 genes have significant variability in their structure, meaning the number of copies and variants of the gene can differ from person to person. This does not normally happen with most other genes, making C4 a gene of interest.

This graph shows the C4 gene on chromosome 6 towering above all other genes that have been linked to schizophrenia, indicating that C4 poses the strongest risk for the disorder.Image credit: Psychiatric Genomics Consortium

The team was surprised by their results; they found that specific C4 gene structures could predict C4 gene activity in the brain. What is more, they found that certain C4 gene structures in the brain led to increased expression of particular forms of C4 that were associated with increased risk of schizophrenia.

In detail, the researchers found that the more a C4 gene structure led to the expression of the variant C4A in the brain, the greater a person's risk of schizophrenia.

C4 'prunes' synapses to increase schizophrenia risk

Next, the team set out to gain a better understanding of how certain C4 gene structures increase the risk of schizophrenia.

The researchers adapted a molecular genetics technique previously used in mouse models to study the "pruning" of synapses - the connections between brain cells, or neurons - and the role of C4 in the immune system.

Using this adapted method to see what role C4 plays in the brains of mice, the researchers found that the gene is key for synaptic pruning - the process by which synapses are streamlined, which normally occurs in late adolescence/early adulthood in humans.

Specifically, the team found that C4 activity was required in order for a protein called C3 to be transferred onto synapses, which acts as a signal that the synapses should be pruned.

Additionally, the researchers found that the greater the C4 activity in the brains of the mice, the more synaptic pruning they experienced during maturation.

The team says their findings may explain why schizophrenia tends to develop in late adolescence or early adulthood; excessive synaptic pruning caused by increased C4 activity at this point in time may trigger symptom onset.

The results may also explain why some people with schizophrenia have a thinner cerebral cortex with fewer synapses. The cerebral cortex is the outer layer of the brain that plays a role in memory, language, intelligence and consciousness.

What is more, the researchers say their findings support the theory that components of the immune system play a developmental role in the brain, rather than just aiding the fight against infection.

"The same proteins are doing one thing in the periphery for immunity, and another thing in the brain," says McCarroll. "It's a clever way nature reuses the same molecules for different jobs."

A 'crucial turning point in the fight against mental illness'

While the research is in its early days, the findings undoubtedly represent a breakthrough in the understanding of schizophrenia development.

Talking to The Washington Post, Steven Hyman, director of the Stanley Center, hailed the research as "the most significant mechanistic study about schizophrenia ever."

"I'm a crusty, old, curmudgeonly skeptic," he added. "But I'm almost giddy about these findings."

And it is no wonder scientists are so excited; discovering that the C4 gene may play a key role in a person's risk of schizophrenia may open the door to strategies that prevent the illness.

"This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics," says study coauthor Beth Stevens, of the Department of Neurology at Boston Children's Hospital.

"We're far from having a treatment based on this," she adds, "but it's exciting to think that one day we might be able to turn down the pruning process in some individuals and decrease their risk."

Commenting on the results, Bruce Cuthbert, acting director of the National Institute of Mental Health - which helped fund the study - says:

"This study marks a crucial turning point in the fight against mental illness. Because the molecular origins of psychiatric diseases are little-understood, efforts by pharmaceutical companies to pursue new therapeutics are few and far between.

This study changes the game. Thanks to this genetic breakthrough we can finally see the potential for clinical tests, early detection, new treatments and even prevention."

Next, the team hopes to create mouse models with the human C4 variants associated with schizophrenia risk. They aim to find out more about how C4 contributes to synaptic pruning, and to determine whether such pruning may play a role in other neurological conditions.

"In this area of science, our dream has been to find disease mechanisms that lead to new kinds of treatments," says McCarroll. "These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops - something that has been greatly needed."

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Comments(5)

I enjoyed reading this article. My first introduction to these findings was in a newspaper article. Based on this article I feel we are on the threshold of finding other genetic links to mental disorders. Something that I have felt was the case, not only for mental disorders, but also for other health problems that researchers are searching for treatments or a cure.

This article and the way that this research has generally been portrayed within the mainstream media is actually extremely misleading. Let me explain:

The correlation between the observed increase in the C4 protein and the increased likelihood of developing psychosis/schizophrenia is only .25 percent (that is 0.25%). To put this in layperson's terms, for a person who has this particular genetic anomaly, this increases their likelihood of developing the symptom criteria for schizophrenia during their lifetime from about 1% to about 1.25%. To put in perspective just how insignificant this correlation really is, psychosocial factors (such as Adverse Childhood Experiences and trauma) have demonstrated robust correlates hundreds of times stronger than this. For example,a major Netherlands study found that victims of child abuse were 9 times more likely to go on to develop psychosis, and that the victims of the most severe child abuse were 48 times more likely to develop psychosis (Janssen et al., 2004). And in 2007, a UK study went over the records of 8,580 participants to identify the correlations between a broader array of childhood trauma and psychosis. They found that individuals with 3 types of trauma were 18 times more likely to have subsequently developed a psychotic condition, and that those with 5 or more types of trauma were 198 times(!) more likely to have subsequently developed psychosis (Shevlin et al, 2007).

Now compare this with the study presented in this article--this study is generally considered to represent the highest correlation ever found between a genetic anomaly and the development of psychosis, and yet such an individual is not even twice as likely to develop psychosis than the average person. Hmmm... so we have a number of major research studies demonstrating correlations of up to 198-fold for childhood trauma and other adverse psychosocial factors compared to not even 2-fold for the strongest genetic correlation ever found. And yet, which of these studies captures the world's headlines and has the greatest impact on health care funding?

As a clinical psychologist having done extensive research on psychosis/schizophrenia and recovery, I find this state of affairs tremendously tragic. We have very clear evidence that we can immediately and radically reduce the onset of schizophrenia/psychosis and radically increase its rates of recovery by targeting psychosocial factors, and yet this is all but ignored by the mainstream media and health care budgeting throughout most of the Western world; while the genetic research demonstrates far, far, far weaker correlations than psychosocial factors, and offers nothing more than the very slim prospect of some yet-to-be-discovered genetic-based treatment in the unforeseen future, and yet it is the genetic and biologically-based research that gains the lion's share of funding and attention.
You can find a very good article discussing some of these problems with the research study on CR here:
http://psychintegrity.org/breaking-news-the-cause-of-schizophrenia-finally-discovered/

In nature,there is an existential cause has establish schizophrenia condition in the basic nature (biological/psychological).
But there are 4 main questions:
1-What is cause of schizophrenia?
2-What is cause of mental symptoms disorder of schizophrenia?
3-What is cause of behavioral symptoms characteristics of schizophrenia ?
4-What is cause of brain chemical imbalance of schizophrenia?

Some belief that: the brain chemical imbalance is the cause of mental disorder,,the mental disorder is the cause of behavioral disorder,,and there is an ill gene expresses about its illness/disease causing the brain chemical imbalance manifestations.
But,it is seems that there is no clear answer about the question :what is the cause of schizophrenia ?
Therefore we need clear definition to the term "schizophrenia" before asking about a cause for it !

In the case if you think that, the whole schizophrenia condition is a specific expression of an ill gene through producing the sums of chemical imbalance, mental symptoms and behavioral deviation,it is hard to prove or answer about many other related questions.
For example: a schizophrenic not born but made in early 20s (top of healthy power) and there is no specific gene for schizophrenia be known in any age !

All questioners asking about the cause of schizophrenia ,while give no attention/interesting to just know what is existent features of the case so-called schizophrenia which has been emitted suddenly inside the biological/psychological nature and be felt independently by a human being while he was in the early 20s of age !

To ask suitable question about cause of schizophrenia,you should distinguish between 2 types of symptoms:
1- The diagnostic symptoms (the sums of all internal or/external of disorder symptoms -excepting the things so-called hallucinations)
2-The existential symptoms (the sums of inner existential features of the things so-called hallucinations)

what is different between the diagnostic symptoms and existential ?
The schizophrenia case itself has expresses about its existence inside the biological/psychological nature of human being through all existential features of the things so-called hallucinations.
While all aspect of diagnostic symptoms are the result of functional activities of the hallucinations over the mental / biochemical processes which has been running in mind-brain of the person !

Therefore:
(1)-the schizophrenia case itself is the things so-called hallucinations,and the vic versa is correct !!
(2)-The hallucinations is the cause of all types of symptoms internal or/external ,biological or/psychological or behavioral
(3)- The hallucinations is the actual cause ,who is decoding and coding the schizophrenia case itself and all types of disorders.

So we have 2 questions: what is nature of hallucinations as it as in itself?
:What is the cause of hallucinations ?
(What is the factor who can synthesis/creation the existentialism material of the things so-called hallucination)
In other words: what is the gene who have the creative characteristics which make it be able to create the hallucinations inside the biological/psychological nature of human being ?)

In sums, you should deal with the term schizophrenia and hallucinations as both of them are one single thing in the nature , so that searching about a cause of schizophrenia is means in the practice action, searching about a cause for the things so-called hallucinations !!

Now we have new look to the actual reality of the phenomenon so-called schizophrenia , help us to achieve real understanding /explanation building on simple facts:
1-The internal features of schizophrenia case in reality is the features of the things so-called hallucinations
2-The whole case of schizophrenia itself is the details of things so-called hallucinations
3-the term "schizophrenia" is just a name (phonetic pronounce) to call unknown phenomenon,while term "hallucinations" is indicates to actual existential features and many types of functional characteristics of new things that has been located inside the biological/psychological nature of the victim in the early 20s of age
4- In nature of any schizophrenic person,the hallucinations are real existential things which they have the full ability to act and behave internally inside time-place of human basic nature specially over every single mental process output causing all types of disorders, , while the schizophrenia is just a phonetic word
5- When you indicate to the internal case of schizophrenia in any schizophrenic person,in nature you indicate to an existence and functions related things so-called hallucinations which be felt by any schizophrenic person,while you and any schizophrenic person can not touch the phenomenon so-called schizophrenia internally because it is just a word coming from the mouth
6- The hallucinations is the only internal condition,case or phenomenon inside the schizophrenic and there is no any type of conditions or phenomena at all,but most people have using term "schizophrenia" instead of using term "hallucinations" , and considering the hallucinations a single symptom of schizophrenia symptoms (A result of schizophrenia),, this consideration makes understanding of reality a mission impossible !
*- Because:
-The hallucinations is the only inner condition,its activity causing the disorders in the higher mental knowledge processes , the biochemical background and behavior outputs,while schizophrenia do nothing because it is a phonetic word
-The hallucination is locating as the inner existential case ,and behaves as the functional cause who is synthesis all types of disorders (the sums of so-called schizophrenia symptoms), this means that the hallucination is the whole condition and the cause in the same time AND it is not a symptom of schizophrenia or/ a result of any biological/psychological action/reaction process or else !

The setup of occurrence : in early 20s of age, suddenly ,a package of existential features has been emitted in the area of inner psychological world of the human being, whereas he feels,sees,hears,touch and coexistence with all details inside himself independent about the views of all external viewers,these features so-called hallucinations, they are starting to act and behave to object the pathway of every mental sign has coming from brain region in the direction of the conscious mind, repeating the cognitive content of the sign by transformation the mental sign into spoken mental message, and repeating again and make radical change in the data content during the second repeating process,and printing the changes ( distorted data ) in the conscious mind,so that the mind have become a recipient of false data every 3 seconds,one after one without stopping all possible time of awake ,,this false spoken higher data which be broadcasted by action of the things so-called hallucinations play the main role to synthesis all type of cognitive disorder processes related any condition of the daily life events, the high speed of the process and the rate of sequence causing the disorder in the biochemical background ,in SUMS,the hallucination activity is the clearest factor who is coding and decoding the world of disorders through its impacting on the pathway of the mental sign which has coming from the brain to mind ...there are endless explanation to the process as it as in its actual reality outside the theoretical imaginations !

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